There has been a long-standing interest in gaining further insights into rare tumors whose etiology is poorly understood. At present, this project is focusing the majority of efforts on four tumors--nasopharyngeal cancer, biliary cancer, liver cancer, and multiple myeloma.Nasopharyngeal cancer (NPC) has a very distinct geographic and ethnic distribution, occurring at high rates among ethnic Chinese from southeastern China and at much lower rates among Caucasian populations. While infection with the Epstein Barr virus (EBV) is believed to be necessary for development of the cancer, other factors, both genetic and exogenous, are also thought to be important. To investigate genetic, dietary, occupational, and behavioral factors related to the etiology of NPC, two studies were conducted in Taiwan - a case-control study of approximately 1,000 individuals and a multiplex family study of approximately 3,000 individuals (350 families). To date, our results suggest an association between risk and specific variants of the enzyme CYP2E1 and several DNA repair genes, specific patterns of HLA and KIR genes, and long-term cigarette smoking. High intakes of nitrosamines and nitrite during childhood and weaning also were associated with increased risks. Occupational exposures to wood dusts also appeared to affect risk; in contrast, formaldehyde exposure was not a significant risk factor. Exogenous risk factors identified within our family study were similar to those observed from our case-control study. Evaluation of gene expression profiles from nasopharynx tumor and normal cells suggest that genes involved in DNA repair and in the metabolism of nitrosamines are involved in NPC pathogenesis. Results from our tissue-based expression studies also suggest the possibility of loss-of-heterozygosity on the telomeric end of chromosome 14 in NPC, and that EBV gene expression within NPC tumor cells affect the expression of host genes involved in immune presentation. This suggests a possible mechanism by which EBV manages to evade immune surrveillance in NPC. Uaffected individuals from multiplex NPC families have been shown in our study to have elevated levels of antibodies against EBV compared to the general population. To evaluate the possibility that these individuals with elevated levels of antibodies against EBV are at increased risk of NPC clinical follow-up of this population is underway. A genome-wide screen is also underway to permit an evaluation of chromosomal regions linked to NPC development within our families.Biliary tract cancers are relatively rate but fatal malignancies. During the last 25 years, the incidence of biliary tract cancer in Shanghai has increased more rapidly than that of any other malignancy. The sharply rising trend suggests a change in the prevalence of risk factor or interaction between these factors and genetic susceptibility. To elucidate these factors, we conducted a population-based interdisciplinary study of biliary tract cancer. More than 3,000 subjects were enrolled in the study, including over 600 biliary tract cancer patients, 900 gallstone patients, and 1,000 healthy controls randomly selected from the population. A structured questionnaire was used to elicit information on epidemiologic risk factors, including smoking, drinking, diet, medical history, and reproductive factors. The study had a strong biochemical and molecular component with an extensive collection of biological samples, including serum, DNA, gallstones, bile, and tissue samples. Molecular data from this population-based study show that these three subistes have distinct molecular changes, including mutations of beta-catenin, p53, p16, and K-ras.